Car Wreck on ME/CFS Patients ‘Oxygen Highway’…

Clean vs Dirty Energy Production

Keep your eyes on the oxygen molecule. Your body thrives on it. It’s at the heart of your aerobic energy production system. When it’s working correctly you’re filled with clean, abundant energy. When its not you’re in trouble.

You have a clean and efficient energy producing system and a ‘dirty and inefficient energy producing system. Guess which one is broken in ME/CFS?

Multiple systems explode into action in order to get that oxygen to your muscles when you exercise. You breath more deeply and your heart pumps harder and faster to transport it just as quickly as it can to your cells. That heart/lung/muscle connection is the oxygen highway.

You have a second (mostly backup) energy production system but it’s a dirty, inefficient and even painful system to use. Called anaerobic glycolysis it mostly kicks in only after your aerobic (oxygen-using) energy production system has pooped out. If you exercise long and hard enough (or if you have ME/CFS – not very long and not very hard) the pain and fatigue you experience when you switch to anaerobic system is unmistakeable.

As soon as you make that switch – at what researchers call your ‘anaerobic threshold’ – toxins are going to start building up in your muscles and you’re probably not going to be exercising that much longer. ( ‘Aerobic threshold’ might be a better name for a switch point that represents the end of clean (ie aerobic) energy production, and a dependence on anaerobic metabolism.)

At that point things get complicated quickly. With anaerobic glycolysis comes lactic acid, and with lactic acid comes lactate, and with lactate comes CO2, and with CO2 comes a big problem. CO2 displaces oxygen – the life blood of our system – so it’s got to be removed fast, and so into the blood and out the lungs it goes. As the CO2 levels in your blood rise your breathing rate speeds up automatically just to get it out of your system.

A ‘Beautiful’ Test

The beauty of the VO2 max test is that it documents all of that. As you exercise it’s measuring your heart rate, how your lungs are doing, the amount of oxygen in your blood, the amount of CO2 you’re getting rid of, etc. It can precisely tell when your aerobic oxygen system poops out and your anaerobic system clicks in (and CO2 starts pouring out of your lungs.) It’s hand-made to detect energy metabolism problems.

The CPET maximal energy test measures both heart and lung functioning

A low VO2 max (or anaerobic threshold) test result means you’ve quickly sped through your aerobic energy cycle and slammed into your anaerobic threshold way ahead of schedule. That walk to the store now seems like a marathon and those bike trips you used to enjoy – don’t even think about them. Somewhere on your oxygen highway you’ve got a wreck…

There’s a big proviso to this. The VO2 max test is very revealing but only if you do it the right way. The energy production systems of most ME/CFS patients will ‘rise to the occasion’ in a one-off exercise test and produce normal results. That turned researchers off to exercise tests until Workwell (Pacific Fatigue Lab back then) showed that these seemingly ‘normal tests’ were leaving big potholes in ME/CFS patients ‘oxygen highways’. The next day most of them people were not able to get back up to speed on an exercise test.

According to Workwell investigators, that’s an unheard of finding in the medical world. Heart, kidney and even lung disease patients can jump on the bike and produce the same amount of energy the next day….but ME/CFS patients couldn’t.

That, of course, means the test-retest protocol could prove that post-exertional malaise – a term introduced to the medical lexicon by ME/CFS researchers – is biologically based. Exertion, after all, is a function of energy; no energy – no exertion

In this two-day test-retest study Workwell investigators were looking to validate their findings from that earlier study.

Let’s see what they found.

The Study

A team of exercise physiologists from the Workwell Foundation had 51 people with ME/CFS and 10 healthy, sedentary controls exercise to exhaustion on a bike two days in a row. They measured their heart rates, blood pressure, oxygen consumption, oxygen levels in the blood, lung functioning, CO2 levels ,etc.

The chronic fatigue syndrome patients and the healthy controls were similar age, height, weight and had similar BMI’s. (The controls were actually quite a bit fatter but not ‘significantly so’ statistically :))

Findings

Couch Potatoes Crush ME’/CFS Patients

First Day – On the first test the two groups looked the same. (The people with ME/CFS had consistently lower results but not low enough to be statistically significant. That probably indicated a number of ME/CFS patients did have significantly lower test results but that the group as a whole did not. )

The couch potatoes demolished the ME/CFS patients in the repeat exercise test

Second Day – the second day was a different story. Placing in the lower 10 percentile in fitness, the healthy controls were certified couch potato’s, but they looked like Olympic athletes compared to the people with ME/CFS. Flabby muscles and all, they were able to jump on the bike the second day and repeat their results.

The ME/CFS group, on the other hand, dropped a full 40% in the amount of energy they were able to produce at their ‘ventilatory threshold’. (If you’re into physics that was about 8 watts of energy).

(Your ventilatory threshold occurs when you’ve exhausted your aerobic energy stores and have begun pumping out lactic acid. VO2 max, the better known test in ME/CFS, measures the amount of energy you produce at your peak level of oxygen consumption. Ventilatory threshold is probably a more accurate measurement of post-exertional malaise because it clearly identifies that you’ve entered into your ‘dirty energy’ production phase.

Workwell’s first study found more evidence of VO2 max issues; this one found more evidence of ventilatory threshold issues; both findings suggest an abnormal metabolic problem is present. It will take time and larger studies to determine which is more prevalent in ME/CFS.)

Deconditioning Not A Factor

Deconditioning was not the cause of the ME/CFS patients declining ability to exercise. If it was, the deconditioned healthy controls would have met the same fate. Nor was lack of effort. An important facet of the full cardiopulmonary (heart/lung) maximal exercise test is that it (and it alone) physiologically determines whether you’re giving your all or not…

Their CPET scores (RER) showed the ME/CFS patients gave it their all on the first test, and when they came back for the second day, they gave it their all on the second test. That’s no surprise; people with ME/CFS are rabid for answers, and they’re willing to go through some pain to get them. Anyone who thinks otherwise (aka a skeptical research community) doesn’t know this group.

(The problem, by the way, is not finding ME/CFS patients who are willing to put themselves through a second test but finding sedentary controls who will.)

High, High Accuracy Rates At Determining Who’s Who

Workwell hit the mark identifying all ME/CFS patients correctly using the results of their exercise test

Remarkably, all the ME/CFS patients and 9/10’s of the healthy controls were identified correctly simply by looking at the test results.

That suggests two things; one – a) this test is very robust; and b), at least for me, it starts to erode the idea of an illness permeated with subsets.

This was, after all, a pretty heterogeneous group – both newbies (just 6 months in) and oldies (30 years with ME/CFS) participated – and both demonstrated what appears to be a unique metabolic problem. Yes, there is heterogeneity; some people with ME/CFS have lower VO2 max scores, and some have lower ventilator threshold scores, but the key is that most people with ME/CFS appear to have an unusual metabolic abnormality that keeps them from being able to exercise much.

Too Harsh? Maximal vs Submaximal Effort Test

Questions have been raised, however, whether two-day test-retest trials are ethical because of the temporary pain they cause. That is a question probably best answered by the patients who choose to participate in these trials.

Staci Stevens reports, however, that Workwell rarely sees ‘adverse events’ in these tests, and that people needing heart and kidney transplants routinely do them. In fact, patients want so strongly to contribute that Workwell ‘frequently’ advises severely ill patients who want to do the second test, not to. Dr. Peterson and Dr. Lapp have been doing CPET testing for years without safety issues. This is not to say ME/CFS patients aren’t in pain after the test but they’re not irreparably harmed; they simply require more time off (from days to weeks) to get back to baseline.

Several factors make maximal energy tests the tests of choice in ME/CFS

Staci noted that recovery time in submaximal and maximal effort tests is about the same, and that patients actually exercise longer on the submaximal test. (In VO2 max tests you’re on the bike pedaling about 8 minutes).

While submaximal exercise tests can provide useful information, substitutes for the Stevens protocol (2-day test-retest maximal exercise study) simply don’t exist. For one thing, the submaximal test results have not been validated in ME/CFS. For another, a skeptical research community being presented with highly unusual results – needs to have all the T’s crossed and I’s dotted to accept them. The test-retest protocol does that. The submaximal test does not.

ME/CFS patients inability to reach age associated heart rates, etc. during exercise (‘chronotropic intolerance’ ) means they’re at risk of being accused of not providing full effort in submaximal exercise tests. Because maximal exercise with CPET actually validate a state of physiological exhaustion has been reached, they do away with this concern. All that’s left at that point is for exercise physiologists to gulp and try to figure out what’s going on. (A favorite fall-back thus far has been “your instruments must not be calibrated right”. )

Reality Check

Under normal circumstances most activities of daily living require energy below ventilator threshold. However, if VT occurs at very low levels of oxygen consumption and/or a very low workloads then activities of daily living may exceed VT….Snell et. al.

This study involved an exercise test but we’re not really talking about exercise with ME/CFS – we’re talking about daily activity levels. In this brief passage Snell et. al bring home the point that in ME/CFS it’s more about being able to engage in the day-to-day activities of normal life than going jogging.

I imagine that’s a very hard message for researchers who dismiss ‘chronic fatigue syndrome’ to get. I suspect many researchers shy away when they hear of the really disabled people with ME/CFS because it just doesn’t fit in their reality. Not many disorders, after all, cause that kind of debility.

That will take time to get across – and more studies like this.

Foundations Not Cracked Yet

There’s no denying Workwell’s influence; exercise and stress tests are now commonly used in ME/CFS studies but the foundational shift that I thought (and I think they thought) we were on the cusp of when I wrote “Cracking the Foundations’ five years ago, hasn’t happened. Neither the ME/CFS or the outside research community have embraced the full 2-day test-retest protocol. Aside from this one, just one study in the past five years has attempted to validate Workwell’s original study (it succeeded).

We’ll look more at the crash on ME/CFS patients ‘oxygen highway’ in future blogs

(No studies, furthermore, have appeared in Science or Nature on the bizarre metabolic abnormalities present in ME/CFS; yes,-I was dreaming big when I thought that would happen, but if these metabolic problems really are unique to this disorder, why not? :))

This means that instead of getting at the cause of the metabolic abnormalities present in ME/CFS Workwell is still trying to prove they exist. It means that GET has not been reinterpreted within an understanding of the metabolic problems present in ME/CFS. It means that exercise programs that fit ME/CFS patients physiology are not the norm. It means that worries about ‘effort’ still exist. It means this disease still gets a psychiatric slant in many quarters. It means that a core aspect of ME/CFS is not getting fully researched.

It’s astonishing to me that an easily validated, readily available and non-controversial technology that appears to explain post-exertional malaise – the key symptom in ME/CFS – has not been embraced. I’m shocked that we’re not further than we are but we are moving forward.

Three test-retest studies have had similar results and Betsy Keller at Ithaca in New York is publishing a fourth. An exercise test (type undetermined) appears to be on the boards of the CDC big multi-center study. A test-retest study by the CDC that finally pushed these findings into the bigger journals and into the news would be a huge win.

To reiterate the CPET maximal exercise test-retest

smashes the deconditioning argument to bits

provides a metabolic basis for the exertion problems in ME/CFS

relies on commonly used equipment that has been used to validate dysfunction in many disorders (unlike much cutting-edge research in ME/CFS).

provides the best evidence for disability possible

appears to identify a core issue that many people with ME/CFS, young and old, highly disabled and more functional share

can differentiate between people with ME/CFS who have metabolic issues and people who are equally low functioning but don’t have them. Thus its an excellent way to subset patients prior to studies

This study provides further validation that something has gone very wrong in ME/CFS patients energy production pathway. In my opinion if anything deserves more study in ME/CFS…it’s this…

This is part one of a series of blogs on CPET exercise testing and ME/CFS. Coming up shortly…Identifying the Wreck on ME/CFS Patients Oxygen Highway.

Comments

I agree this is a pivotal study for ME/CFS, which makes one question why the powers that be, ie.,. Konegel’s group,Research 1st, etc. haven’t designed any studies around trying to answer the big question- WHY? From there of course how to fix it!

I also agree it casts doubt on the subclasses issue, which I feel is more like the many “types” of MS still being MS.

I’ve also wondered of the politics of “Workwell” or whatever leaving UOP? Seems like we just can’t get no respect!

I don’t really understand it either. Since I first learned about this research it went right to the top of my list of potential game-changers in ME/CFS.

To their credit the CAA funded the first study; I don’t think it would have happened without them. I don’t think, but I’m not sure, that Workwell researchers applied for the last go-around.

My guess is that Workwell has the only exercise physiologists in the field and they don’t have many natural allies. Other research groups are not going to pick this up because they don’t exercise physiology. I was surprised that validating these results, though, wasn’t the top of OMI Merits priority list but I don’t believe it even made the list.

The CDC study at this point, to my knowledge, does not include a maximal exercise test let alone a test-retest study.

Workwell has been pounding on the door for five years now. Snell has given talks everywhere you can think…Everybody knows about this…I think its time for this research to get some serious money..

The UOP situation? I don’t know what happened there but I don’t think anybody was happy it happened.

Is not the work by Dr. Nancy Klimas and Connie Sol using VO2max work based on the premise that Staci Stevens and the team uses?

Their recommendations seems to also support that of Dr. Chuck Lapp who suggests that failing the VO2 Max tests, people with CFS/ME need to use the 60% maximum heart rate figure to pin point their anaerobic threshold.

Working at that rate with a heart rate monitor has shown me that my breathing rate goes up when I reach the 60-65% level. I now can use my breath to tell me when to stop, stand or slow down for a bit until my breathing level returns to below my personal anaerobic threshold. I have been able to walk further or do more after an elevated pulse rate if it I try to quickly back off the intensity of what I am doing.

Yes, several prominent doctors including Dr. Lapp, Dr. Enlander and Dr. Klimas use exercise machines to assess their patients and devise treatment regimes for them. That’s all due to Workwell’s work. The big step is getting the 2 day test-retest maximal exercise study out into the research world so that the metabolic dysfunction becomes understood and ultimately treated..:)

With regard to working with a HR monitor, I too have found it very useful in my struggle to figure out to exercise with CFS/ME. I started walking while keeping my HR between 60-65% of max as I had heard a running coach uses in training elite runners during their training runs. It was an eye opener how slowly I had to go up the hills. I realized that just walking without the HR monitor was like others walking quickly on the level and running up every hill. Now I can pace myself to me and don’t need the ‘recovery’ time like I needed prior to gaining this knowledge.

I’m totally agree with you that research in this subject is needed. I went to Ithaca College to be tested with Betsy Keller because there’s nothing done in Montréal. I think it’s the best way to identify cfs patients before any study. I push real hard here on my doctors to have this test retest done. Hope I will succeed one day!

Dutch cardiologist Prof. F. Visser is doing the two days exercise test with ME/cfs patients. I dont know if he is going to publish about it. I will ask him in a live chat what his plans are and if he is doing it the same way.

That’ s great to hear…I’m looking forward to hearing what he’s doing…There are several small groups that are doing this – mostly by themselves – hopefully it will all end up in one big eye-opening study…(that shows up in Nature or Science :))

Thanks for the plug for my blog on the same study, Cort – but no one can tell the story quite like you do.

The low energy efficiency at anaerobic threshold is fascinating and could lead to a breakthrough, but because the finding is so striking I would like to see it replicated before getting really excited about it. There again, I am rather hard to get excited.

This just so fits for me that I’m excited. I was excited five years ago. This is the third study to find metabolic problems using the Stevens Protocol. I agree we need larger and more rigorous studies. We certainly deserve them..

Very Interesting study but no surprise. Question is how can this translate into potential treatments or cures? What is the root cause of this disease? Is it the immune system ect or is it an oxygen problem that’s causing this multisystem disorder? we have to get to the root issue?

Agreed! Once they establish that this is mucking up the energy in ME/CFS then they can dig deeper. I think they’re getting at the root here and its a pretty darn dramatic root. It makes intuitive sense to me…The autonomic nervous system problems tie in here and so do the immune problems if Dr. Klimas is right.

We are still plagued by a huge problem – getting articles published by the mainstream medical journals. That an article hit Science was almost beyond belief. Doctors with specialties in other areas, accustomed to being published in the best journals, will often find themselves inexplicably turned down by the same journals. Seems to be a bit of a bias against publishing on ME-CFS. A serious problem.

As Simon said – no-one tells the story quite like Cort; and no-one sounds a note of caution like Simon.

Good to have both.

This struck me as exciting and depressing at the same time for reasons already discussed.

But I also wish that sometimes, although not the scientific way, researchers would indulge in just a little speculation as to what might be going on.

Its not as if we have some sort of ‘alien’ physiology after all. Surely someone could hazard a guess? Exercise intolerance is far from unique to ME/CFS but what about this re-test effect. Is this unique in human physiology? Has it ever appeared in animal models?

Diabetic autonomic neuropathy (DAN) is of the very few conditions I’ve come across where extreme caution is advised when considering rehabilitative exercise. Might there be clues there?

I too wish researchers would publicly step and start spinning some theories. I’ve tried to get the IACFS/ME to have a session devoted to that at their conference for the last two conferences. They haven’t been interested…

I will have ‘some’ stuff on what Workwell thinks might be going on in a future blog…I imagine researchers are doing that at the Banbury Meetings every year but we never hear what goes on there.

They are familiar. They funded the first Workwell test-retest study…and they’ve done webinars on the subject. They’re also funding studies in which exercise is included but not test-retest studies so far as I know.

I went to CFIDS Association event here in LA a few months ago called Catalyst Cafe. Dr. Suzanne Vernon gave a presentation about Research 1st and mentioned five or six CFIDS studies being done. One was an exercise test, and I’m not sure but I don’t think it was this one.

There was an informal discussion afterwards and she was stressing the importance of finding a biomarker. I asked if the two day exercise test could be considered a biomarker. She was pretty dismissive of the idea. She laughed and said it was torture. She said they are used for disability cases but researches have trouble replicating the studies. They are more interested in finding a simple blood test biomarker. That was the impression I got.

Myself, I am very interested in getting the FDA to approve the two day exercise test as a biomarker. It shouldn’t be so difficult to replicate. It can be torture, but it’s better than nothing.

Well. I don’t really understand her comments.. This is the third of three positive test-retest studies; this one did find ventilatory threshold was significantly different not VO2 max but as Simon points on in his blog, Dr. Snell says they’re seeing both in ME/CFS and neither in healthy controls and both are indicative of what appears to be a unusual metabolic abnormality.

That’s a pretty darn good track record; it’s actually alot better than most other areas and yes, we do need big, rigorous studies to determine how prevalent it is….and we don’t have those yet but we sure have some tantalizing findings.

The difference between these and other studies is that this is so easily tied to post-exertional malaise and disability. Three’s a reason disability judges accept it so readily (and not many other things); it’s because it’s clearly indicative of a SEVERE problem in producing energy. I don’t know (other than an active pathogen) that you can say that about other blood markers in this disorder. I LIKE the disability connection; I think it says alot about how strong this test is.

While researchers elsewhere are searching for their mystery protein or immune factor that they hope will at some point differentiate ME/CFS from other diseases, we have a test result right now that we know is a) not present in many other disorders b) is well understood and validated in the research community….Why would you not throw money at that? Because it’s painful? The headache I got from my spinal tap was excruciating but I would do that again if I felt it might provide the answer for my 30 year case of ME/CFS…

I’m just now reading through all of these comments , you guys are awesome! I feel like throwing a party for you all…it’s amazing how close to home this all is for me. I’ve been dealing with this for 5-6 years & the post exertional malaise is the biggie & what is so hard for me to accept (I’m an ex-runner & most of my friends are athletes). I would love to be part of a study & I think here in Boulder, CO (where I live) there are others like me. I need to do more…but I’m always so sick & tired :P.

Note: This study does not proof PEM post-exertional malaise but post-exertional fatigue! Read the abstract correctly. However this is a verry important finding. In the Netherlands dr. Vermeulen has found the same problems. He still do this 24 hours exercise CPET test. He says an abnormal low AT/VT is typically for ME. Professor dr. Visser also do this test. I hope he will publish his results one day. Dr. unger stated that the CDC is doing a singel exercise test. This is a big problem to validate the study of Snell.

Thanks for pointing that out re ‘malaise’…Fatigue could fit under the post-exertional malaise category because it is a symptom that flares up after exercise (although I get it wasn’t referred to in the study). . Workwell has shown that numerous symptoms flare up after exercise – http://www.ncbi.nlm.nih.gov/pubmed/21682669 – so while using malaise wasn’t particularly accurate for this study – I think it fits – but thanks for the rigor.

Vermoulen was going to continue his exploration of exercise’s effects in ME/CFS. I haven’t been able to find out if he did. I’m trying to do that…

Cort, I raised this once before but no one responded. Dr Ramsay has found an intermittent problem with the deformation of some red blood cells which carry oxygen. The deformed cells can’t pass through the smallest capillary walls as they don’t roll up as normal blood cells do.

This deformation can only be seen if the blood is immediately fixed when it is taken. The description of Dr. Ramsay and his discovery is written in the book RAMSAY’S DISEASE Myalgic Encephalomyelitis (ME) And the Unfortunate Creation of ‘CFS’ Dr. L. O. Simpson PhD With Nancy Blake BA CQSW UKCP-Accredited Psychotherapist

Apparently this is a problem in many chronic diseases. Dr. Simpson cites studies that prove this, but it doesn’t seem to have been taken up by researchers.

Can anyone tell me why this research backed finding hasn’t been followed up?

I have all of it…Stress of any kind (emotional, physical and certain types of cognitive) increases symptoms for me..I’m healthier than most but my autonomic nervous system feels like its on a knife’s edge..

My wife & I went on a 7 day cruise to Alaska. I was off my regular daily schedule and rest routine and it didn’t get dark at night until after 10:00 p.m. The last day at sea I spent the day & early evening in bed. After we returned home It took me most of that week to recover to my pre-cruise fatigued self.

When I was diagnosed, I did have to do exercise bike tests, but this was to establish no heart problems rather than to look for features of ME. As a keen jogger and cyclist at the time, it had been my body’s inability to provide me with enough oxygen – leading to palpitations and huge air hunger that nearly split my chest open – that had alerted me to the fact that I was ill in the first place. Doctors would not take me seriously, and, oh how I longed to be able to get access to a full sports’ science lab, which I knew was the best place to investigate my illness. No chance, of course: though sports’ science was and remains, all the rage, getting access to its equipment and scientists for medical purposes, is still impossible unless you are a TV personality promoting your latest diet fad. When will medicine ever get into the 20th century – let alone the 21st!?

I have a bit of confusion over this ‘achieving maximum heart rate’ business. I’ve been bedbound pretty continuously for around 20 months, after trying to exercise myself better, so I’ve seen the typical modern ‘gym’ equipment. This, typically, has a chart showing maximum heart rate for age, prominently before one’s eyes. I had assumed this was there as a warning, not to let my heart rate go too high for my age: not as something I was supposed to struggle to hit! These days I could probably hit my ‘maximal heart rate’ just trying to put my shoes on – assuming I could reach my feet without dislocating my arms!

A further point that I think needs looking at, is the way using large muscles robs oxygen and energy from the rest of the body. For me this is really serious, and, if only GPs would actually include going for a walk with me, in their tests, they could easily see it for themselves, but they prefer to just pronounce scathing opinions from their comfy chairs.

I have been suffering from a tight, dusty-feeling, throat and chest since my relapse. If I go for a walk, as the large leg muscles come into use and force the body to devote its energy resources to them, my chest and throat become progressively tighter until I feel I’m choking and my chest is going to split. While I am walking, my belly begins to blow up so that I end up looking pregnant – I surmise this is because energy required for maintaining abdominal muscle tone, has been diverted to my leg muscles. At the same time my vision becomes steadily dimmer, and more and more blobs get in the way of what I am seeing. My eyes cease to work together and the world becomes a very frightening place. If I get distracted and walk too far I can end up fearing for my life. I also become sensitive to the slightest puff of cool air, or drop of rain, on my skin, which, pretty much sends my body into shock mode.

These are such serious, and easily repeatable symptoms, that, even now, after getting on 30y of putting up with ludicrous psychobabble about ‘anxiety’, ‘panic attacks’ etc. I still cannot believe that no doctor has ever shown the slightest interest in trying to help me find out what is wrong. It really should, with the right equipment, be easy!

I love speculation :)…Dr. Klimas has found that gene expression tests during exercise show that something happens to the autonomic nervous system which then triggers an immune cascade which she believes causes the pain and fatigue we feel. She hasn’t said what exactly she’s found.

Gene expression tests are notorious for not providing ME/CFS researchers with specific results; ie single genes that show up again and again. My guess is that she’s finding gene pathways involved in ANS functioning that are going off the rails in ME/CFS but we’ll see.

It is an exciting idea and it does fit with the emerging idea that the ANS plays a key role in this disorder, which is nice :)..

That could fit in the the ‘dirty energy’ theory if the ANS was not providing enough blood and oxygen flow to the muscles leaving the mitochondria to switch to the ‘dirty energy’ or anaerobic energy production phase.

Several researchers appear to be thinking blood flow is important and its pretty clear it is but while bringing blood flows up to normal via saline and other drugs helps, it’s clearly not the whole answer as well.

Vermoulen pretty much decided, based on his exercise study that mitochondrial problems were not ‘it’ but when I talked to the Workwell researchers they felt that was still a possibility. Vermoulen, if I remember correctly, was focused on blood flows. There’s also the idea that the mitochondria, for some reason, are not picking up the oxygen that’s in the blood. There’s no evidence of reduced oxygen levels in the blood.

I imagine there are a range of possibilities which researchers have hardly touched on…

One of the nice things about the CPET test does is that it does help narrow things down a bit. That ‘narrowing’ will show up in an upcoming blog.

Thanks for this elaborated answer Cort – my , you came up with it in no time!
I will push my luck and try to tempt you in speculating further into this one sentence of your response (you or anyone else interested of course) :

“There’s also the idea that the mitochondria, for some reason, are not picking up the oxygen that’s in the blood.”

– “for some reason” … – any thoughts on it pertaining to an auto-immune issue, e.g. some type of antibody attacking the mitochondria and thus messing up cellular respiration? Or any other reason?

Aha…you see that’s a possibility I hadn’t heard of but, layman that I am, particularly regarding autoimmune issues, I would think that would be a possibility and an interesting possibility at that…Anyone else?

Okay, I will take a stab at this. My doc at Mayo thinks there could be mito issues. He feels that mito testing does not pick up all the problems. They can only test for a few kinds and he thinks there are many more.

With some of us there could be a problem with NO (nitric oxide) This helps with energy and oxygen distribution.

A number of studies in vascular endothelial cells3 and in tissues4,5 have shown that this results in a decrease in consumption of O2 and in its redistribution away from mitochondria and toward other oxygen-dependent targets.6 Thus NO plays a role in the subcellular profile of O2 distribution.
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Also, adenosine has been known to be a player in CFS and in this article it and NO is shown to affect blood flow.

•Adenosine is an important mediator of active hyperemia and autoregulation. It serves as a metabolic coupler between oxygen consumption and coronary blood flow. Nitric oxide is also an important regulator of coronary blood flow.
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These things have a direct influence on vasodilation and blood flow. I posted in another post some conference slides/notes showing that CFS people have a large increase in adenosine with exercise.

It could be helping with blood flow. NO vasodilates the veins and improves oxygen delivery. And it is thought that NO can also play a part in blood pressure regulation.

There is a whole lot of research to understand all this, as there are different types of NO synthesis and it can affect different parts of the body in different ways. Here are some articles you can read.

I’d like to caution seriously ill patients against trying this test. Back in the 90’s I tried the gas ergometry bike test, or at least I believe that’s the correct name – no follow-up with a 2nd test. I’m not lazy and was very motivated to take part in all of the testing provided at a well-known CFS expert’s clinic, but that day I was feeling so weak that I told the tech that I didn’t think it a good idea. He guilted me into doing it, telling me not to worry. I think I came close to finishing the test but I finally lost my balance and fell off the bike (was caught – no problem there). However, I was in pretty bad shape so we returned to our hotel. I was lying on the bed and had this awful seizure, later diagnosed as myoclonus. I have it to this day, although not as severe. Perhaps I would have developed it even without the exercise test because certain drugs, such as Amantadine, later triggered severe episodes as well, requiring a trip to the ER finally. Still, maybe I could have gone a year or two longer before the myoclonus made its appearance if I had just said no to the test. It further irks me that I didn’t stay on the bike quite long enough for any test results and trust me, I tried!

The last day of testing I was given the QEEG and there was no doubt I had major brain dysfunction, though. I imagine it was worse than usual, following that exercise test. That would have been very interesting, to see QEEG results at the beginning of 3-day general testing period and then again at the end.

Overall, I’m much stronger than back then, so would like to offer hope to those still wheelchair or bedbound. It IS possible to improve, even after many years of living with this DD.

Thanks Nan. That was a rough experience. Sometimes it really pays to trust your intuition and I would guess that anyone who feels they are not resilient enough to take that kind of test, to trust their intuition and not take it.

I know somebody who’s had myoclonus…Can you say how you were able to get better?

I know I should have said no to the test, but the tech was so insistent and I didn’t want to appear to be a wimp, I guess – BAD decision.

I should have made it clear that I still have myoclonus almost every day, although no longer have the SEVERE attacks (think Linda Blair in The Exorcist 😉 caused by exercise, certain drugs and overstimulation. The night of my birthday was pretty rough, though, with worse myoclonus than usual. We had gone to a restaurant that was unusually loud and also played mini golf, so there was just too much activity and noise that day. I can’t tolerate any of the usual seizure meds although Ativan used to help as long as I didn’t take it more often than every 2 weeks or so. Otherwise, my system seemed to build up an almost instant tolerance to it and it did nothing at all. My neuro didn’t think it safe for me to take anyway, so all I have is Xanax, taken at bedtime and occasionally if we’re going out. Its not much help but better than nothing.

As far as my overall health, about 12 years ago I just started to grow stronger for no particular reason I can see. Its true that my sleep had improved in that I no longer awoke at 3 A.M. every night thanks to the right drug combo (Xanax, Vicodin and possibly cal/mag has helped too) but otherwise, I can’t chalk the improvement up to anything else. All I know is that one day I felt stronger, as if I could actually make it to the mailbox at the end of our driveway, which I hadn’t been able to do in years. It wasn’t easy, but I made it and just grew a little stronger from there. For the first time in years I could walk through a store or two without needing my scooter or wheelchair. That alone felt like a minor miracle. My balance and slurred speech improved too for several months, although its back to being lousy again. Still, although I have some very bad days, I still have enough good days when I can shop a little and even drive a bit. I’m still quite disabled part of the time and still battle with pain, bad memory and other neuro symptoms but I’ll take whatever improvement I can. I was even able to go on some short hikes while on vacations with the help of 2 hiking poles, resting on lots of boulders along the way, mind you, but it was still a wonderful improvement. I still need my scooter for longer “walks” outside and I still haven’t recovered from my birthday celebration last weekend, so there has certainly been no cure. Still, after being sick for so many years, since 1978, I had thought I was destined to continue going downhill, so I feel quite lucky.

I wish I could offer some helpful advice for those plagued with myoclonus other than to try not to overdo and to avoid restaurants that are loud and echo or other large, noisy groups. Some may need to go further and avoid TV and movies too or use earplugs. Bright sun, lights or anything that amps up stimulation can make it worse too, so sunglasses are a must. Strangely enough, the same things that can trigger myoclonus can sometimes do the opposite, all but paralyzing my muscles….strange…

Thanks Questus, this is much more helpful for patients who are too ill to do exercise testing, and easy enough for any doctor to monitor. If activities of daily living push us over the anaerobic threshold then we need to respect those limits and find out why.

Hopefully you will see my comment regarding mitochondrial blood tests being a potentially safer biomarker for all patients. Suella and Christian have mentioned this, and Cort you should know this if you actually understand ME, please google viruses and mitochondria!

We also need brain scans and immune function tests as biomarkers, and ultimately we should be treated like patients with other serious diseases where they do not have to physically prove their disability beyond the doctor’s diagnosis.

Just this week I watched Dr. Klimas’ videos on the VO2 Max testing for determining our anaerobic threshold and target heart rate to avoid a crash. I called a cardiologist to schedule one so that I can better predict how much I can do, I’ve been guessing (and crashing many times) for the past 6.5 years. However, this article now raises a question for me, since PWCs can perform a one-off ‘average’ on the first day, but not the second day, should I try to have a 2nd day VO2 MAX test done and use that to determine a more accurate AT and target heart rate?

I’m already on disability for CFS. A second Vo2 Max test could be expensive as I don’t know if Medicare will cover it (or the first one for that matter). It might be easier to use the 220 – age * .60 = max heart rate formula, experiment, and just see how I feel doing that. Any thoughts if I should use the day 1 or day 2 VO2 Max test results? It seems like Dr. Klimas just used did one VO2 Max test on her patients, but could it be that might not give as useful information?

My understanding is that they only use one test to base the optimum heart rates on. This actually makes sense; they know that you’re going to relapse after the first exercise test and they want to avoid that – so they find the amount of exercise (heart rate) you can tolerate on the first day…

The goal of the exercise program is to never get to the second day relapse

Excellent article, Cort — you described complex ideas with clarity and you bring them to life (as usual) with your excellent analogies!

I have often wondered why Dr. Klimas, wonderful, respected doctor and researcher that she is, is only doing the 1-day test — after Workwell’s work, it doesn’t make sense to me. It would be great if Dr. Klimas would address this discrepancy. The *only* way for ME patients to accurately measure HR at anaerobic threshold is to do the Workwell 2-day CPET. If patients are too ill to do the 8 minute test, then they can only use the other methods to approximate it (e.g. using the Borg RPE scale, as per Jennie Spotila’s article for CAA years ago), but it’s just that, an approximation.

Even for people without ME, the *only* way for them to accurately measure HR at AT is the 1-day CPET — they just don’t need to do the 2nd day because the numbers won’t change significantly (hence, the CPET as the “gold standard”). But as you’ve written, since Workwell has discovered the significant drop in measures for ME patients only, on the 2nd day, that can include the HR at AT measure as well.

For example, you could have an ME patient do the 1-day test and have their HR at AT measured at 115 BPM, say, but only if they do the 2nd day test would they see that their HR at AT is then 105 BPM, say. This 10 BPM difference would make a huge difference day-to-day if you’re doing this test keep your HR under the point of AT where you’ll help prevent worsened symptoms. You definitely want to know — and use — the lower number, no? Have I misunderstood what you were saying in your comment?

Consider this possibility; the more severely ill have the same thing going on as the less severely afflicted – they just can’t take the test because it’s too difficult.

My understanding is that several studies point away from mitchondrial dysfunction and towards blood flow issues although mitochondrial dysfunction is still a possibility..Time will tell!

I know some studies have been done on mitochondrial functioning but generally by smaller groups that probably don’t get much attention…However with the brain lactate measures popping up maybe that will encourage a deeper look. If the test retest studies get real attention that should prompt a deeper look as well. Maybe somebody else knows more about the mitochondrial side (I’m sure they do! :))

If half the patients can’t take the test because its not just difficult but impossible, then it cannot be used as a biomarker. Blood flow issues are related to mitochondrial dysfunction, the heart needs energy to pump that blood around, and anaerobic energy produces lactate in the muscles, information we have known about for a long time.

There are a lot of contributing factors including the CNS, ANS, infection/inflammation, toxins, blood cell deformities per Ramsay and Simpson etc, but you seem fixated on pushing exercise testing with all its dangers while dismissing all the testable contributing factors. We need funding to follow up these biological markers, not more exercise studies.

Your agenda to push for more exercise testing at the expense of more promising studies doesn’t quite add up, but I appreciated most of the comments. Viruses and mitochondria, you really should be up to date on this important subject.

For CFS sufferers who no longer work and who are stuck with insurance companies claiming that fatigue is a subjective phenomena and not an objectively measurable pathology, well, this simple test-retest proves them wrong in two days! So for that I believe the test is of tremendous value. Plus it hardly requires any further “testing”, it’s basically all done! It just needs to be sent out everywhere and be officially recognized.

That being said, I certainly do you wish just as you Jackofit to see someone getting at the heart of the problem and find out what keeps those mitochodria from doing their job right..

… my apologies for one clumsiness in this comment which is to leave out all of those people, upon whom you had just drawn our attention, who can not even withstand the rigours of such a test, and for those people I agree we indeed need an alternative…

Denise, am thinking Dr. Klimas isn’t doing the two day test because it’s cost prohibitive for most patients, and unless she has grant money for an official study on this it may not be productive for her. She’s got a lot of studies going on.

Jackofit, Am glad you see the beauty of being able to determine your own anaerobic threshold using the formula (from Workwell I’m assuming) in the link I posted. All of us have CFIDS, and some of us have dysutonomia, (POTS, Hyperadrenergic POTS, and autonomic dysfunction are all under the dome of Dysautonomia), and all CFIDS experts and Dysautonomia experts agree on one thing. We NEED to exercise. Starting at a very, very low pace with quite a bit of rest in between small segments of exercise, (that element told to me by Dr, Klimas).

So knowing your personal anaerobic threshold will help you get started. Buy an inexpensive HR monitor wristwatch and get started…Slowly. Go easy, keep a log and try to improve with time. Use the HR monitor, know you anaerobic threshold and avoid PEM. Good luck to us all.

Jackofit, as for CFIDS and mitochrodrial issues…I feel certain Cort is up to speed on this. (He can speak for himself!) Jack, I agree with you that there all CFIDS patients have mito dysfunction, (once again Dr. Cheney had this as one of his lectures to patients 2 DECADES ago about mito dysfunction and lack of ATP), but I think it’s about degree and true mitochondrial disease. I don’t think all CFIDS patients have mitochrondrial disease, but suspect all CFIDS patients are very much compromised in this department.

As for mito disease being included as a biomarker in CFIDS, (as I hope low NK cells may officially be) I think we’re not there yet, but I’m not up to date on what studies are going on with this? Does anyone know what studies are being done?

Good article Cort on the reason for CFIDS and PEM. Is anyone here currently exercising? Walking daily, swimming pool exercises, recumbent bike…?

My guess is that for Dr. Klimas’ purposes – determining exercise limits – and creating activity plans and understanding the gene expression going on – 1 day is enough. From what I can tell she does embrace the two-day test retest trials as a way to highlight the metabolic issues present.

I think that this test is very promising, but have a few big hesitations re if it were to become standard diagnostic criteria, esp when it comes to disability. One is that there are people who are too sick to do it at all, & the way that our disability works, they would be required to do it, or automatically fail to get disability. (I know it’s messed up, but seriously that’s the way the disability people think. I recently went thru the continuing dis eval & nearly lost my disability because said disability makes it almost impossible to do what they wanted me to do.)

Another issue is that there are people with ME/CFS who have delayed PEM, & that might not show up in the two day test, which could falsely “prove” that they don’t have ME/CFS, when they really do.

And, my third concern is that I have had many times when pushing it too far has led to permanent worsening; not just a long crash. I know I am not alone in this. This test has the potential to cause that type of reaction, & not only could it do that once, but if someone is on disability, they have the continuing eval every few yrs, so if every time they do this, they became permanently worse, that could be devastating….and could also lead to my first scenario.

All valid concerns Tammie, I hope this test pushes opens the door so that researchers dig deeper into the metabolic problems present in ME/CFS and then they throw it away because it is difficult and it does exclude people who are too sick. What I want to do is to focus attention – that’s it really; focus attention on this area and if that happens I’m sure they’ll find biomarkers that don’t require 2 day tests or even 1 day tests.

Sheesh Cort . After years and years of pushing the idea of subsets now your becoming a lumper from one studies results. Please inform your friends in the of the research world of this possibility will you?
I’ve always personally felt this is one condition with a wide spectrum, much like autism. Glad to here your open to the idea finally.

Interesting article but no real surprise to ME/CFS sufferers as we observe this on a daily basis. I have suffered with ME/CFS on and off for twenty years, prior to that I was an International Standard middle distance athlete. After years of research into the illness, I came upon purely by chance the workings of Dr Raymond Perrin.
His book : http://www.amazon.co.uk/Perrin-Technique-chronic-syndrome-ebook/dp/B00APDUOOY/ref=sr_1_1?ie=UTF8&qid=1375435866&sr=8-1&keywords=perrin+technique
immediately struck a lot of chords with me and seemed to be the first explaination of ME/CFS that made sense. As a result of reading the book, I started treatment at the Perrin Clinic and two years on can categorically say that not only has Dr Perrin found a quick physical diagnosis of ME/CFS but has also found the root cause of the illness and a treatment. I am happy to talk at length about this, but it is not the reason for my post.
I am now at the stage where I fully understand the illness, its causes and how to control it (& I am by no means a scientist) and am interested in now introducing excercise to my regime, which drew me to your article. Dr Perrin on exercise has one rule : “Always do half of what you think you can do”, which is a good guideline but has no scientific basis.
On reading your article, I was struck by the focus of your work and indeed the title “Busted! Exercise Study Finds Energy Production System is Broken in Chronic Fatigue Syndrome “. What if for a moment you change your focus from Energy Production to Energy Recovery i.e. what if the production system is working normally but the recovery system (i.e. drainage of toxins from the muscles, Blood & Brain) is the part of the system that is damaged. Coupling your studies with the work that Perrin has done could provide a clear treatment pathway – including the understanding of how excercise and the measurement of fatigue could aid recovery for ME/CFS patients

Great article, great research. I do hope more and larger studies get funded and published soon!

Two thoughts: Cort, you mention “pain” as the problem with the test. Certainly it will produce pain for most ME/CFS patients, but not only pain: also most probably a huge relapse/PEM phase with all symptoms going high. For me, it would leave me completely bedbound for weeks, unable to care for myself. Like someone said above: the combined flu-hangover-jet lag-zero energy-super sick state.

I agree with those mentioning that it can’t be a biomarker/diagnostic marker since a large percentage of the ME/CFS population is simply too ill to take an exercise test.

BUT it is important research that can give us recognition plus more clues about what’s going on in the body in ME/CFS. Also, I think the 2-day Stevens Protocol test should be included as an outcome measure in all clinical ME/CFS treatment studies.

Hello to you clever people “, I love you all for doing this for ME & YOU”!! This is very good new,s for us”! ………. This give,s ME HOPE”! I’m soooo sick “of being sick”,! …. No sleep , …. & all the pain that come with this Broken body”,!!!… There is sooo many of us out there”! Stuck in prisoned in own body,s”,!!! Life sentence for us. “,! ….ME20yr on onononon”! … I would defo gladly “,! Do these test”! If they look after ME”,! After the test was done”,! Would be very poorly “,! & very weak”,! Would not like spinal tap thou””,!!….mother of three children … Two grandchildren “,! Would be good for them to see ME ….WELL”,!… If I didn’t have them “”” who I love with all of my heart..!.. I would take my life”! …. & that is a sad thing for ME to say”,! It’s not cos I’m Depressed ” I’m happy if it wasn’t for ME”! …It’s cos it Is a live in HELL”,!!… Nightmare “! Illness to live with”,! & reading this ” .. Make,s sence to my fogggg brain”,! I do get bad chest pain,s sometime,s?? It’s got worse the past 6moth”, so as my pain toll , ” & getting ME down emotionally”, ..& I now no I am not alone “, thanks to my iPad.! So if you need ME.. I’m there. Lots of love to all. Thank you….

Very interesting study summary and comments, thanks.
I have a few comments/questions.
Re: exercise testing – who needs testing?
This study is important to add to the growing differention of ME sufferers from other diagnoses for advancement of the science so that causes and treatments can eventually been identified. So thank you to the participants. Also, the insurance companies, holding the purse strings of our disability pensions (for those of us lucky enough to have them), want some proof that we can’t return to work. This test might be useful in that regard. But otherwise, I don’t think that all those with ME, especially those severely affected and particularly sensitive to post-exertional fatigue should have to do such a test.

Re: rationale for post-exertional fatigue
Dr. Myhill, a physician in Wales has worked extensively with people with ME and done research (3 studies) of the connection between ME and ATP (mitochondrial function). She has an almost overwhelmingly vast, but easily searchable, website where she explains, in ~educated-lay terms these associations and explains why we crash after exertion and so much more. Her website is: http://www.drmyhill.co.uk/. She does ATP testing with all her patients looking, not just at ATP production, but for where in the production and re-manufacture process, eg. to ATP from ADP, that the fault lies to best tailor her treatment recommendations.

Re: exercise prescription
I realize that this study is about assessment but I, like others, struggle with how to exercise.
I was previously active running annual half marathons and working full-time as a physiotherapist until medical retirement about 4 years ago. Dr. Myhill has her patients do high-intensity training, once their ATP has improved. She argues, and this is well corroborated in the exercise physiology literature, that exercising-to-fatigue (more like body builders) stimulate greater mitochandrial growth than other forms of exercise. This must be accompanied by sufficient rest and she has a link to a video from Dr. McGuff’s website (author of Body by Science), http://www.youtube.com/watch?v=5eNBTZiZnLY.

Re: My own exercise
I do the exercises as per Dr. McGuff once every 2 weeks (time for rest and for a few other activities – required or for enjoyment such as gardening or a short hike).
I also go walking (1/2 hour ~3x/week) with a HR monitor staying within 60-65% max HR.
1-2 days/week I will dig or rake in the garden/yard and will do 10 mins of yoga once a week or two. I hike with a rest for about an hour once every two weeks.
I’m getting stronger, able to go faster up the hills while staying in my range, crashing less extensively and for shorter periods, able to make healthy food more often and have increasing sense of well being after about 2 months.

Question: Does anyone know about any research on high-intensity training for people with ME? There’s some on ME and lots on HIT but I’ve found none bringing the two together.
Thanks so much.